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Risk of Breast Cancer Later in Life for Girls Undergoing Radiotherapy Explained

By MedImaging International staff writers
Posted on 02 Oct 2013
Image: Computation model of the developing mammary gland beginning at three weeks of age (Photo courtesy of the US Department of Energy’s Lawrence Berkeley National Lab’s Life Sciences Division
Image: Computation model of the developing mammary gland beginning at three weeks of age (Photo courtesy of the US Department of Energy’s Lawrence Berkeley National Lab’s Life Sciences Division
Exposing young women and girls under the age of 20 to ionizing radiation can substantially raise the risk of their developing breast cancer later in life. Scientists may now have found the answer as to why this occurs. A collaborative study’s findings pointed to increased stem cell self-renewal and consequential mammary stem cell enrichment as the reason.

Breasts enriched with mammary stem cells as a result of ionizing irradiation during puberty show a later-in-life propensity for developing estrogen receptor (ER)-negative tumors. Estrogen receptors, i.e., proteins activated by the estrogen hormone, are vital for the normal development of the breast and other female sexual features during puberty.

“Our results are in agreement with epidemiology studies showing that radiation-induced human breast cancers are more likely to be ER-negative than are spontaneous breast cancers,” said Dr. Sylvain Costes, a biophysicist with US Department of Energy’s (DOE) Lawrence Berkeley National Lab’s Life Sciences Division (LBL; Berkeley, CA, USA). “This is important because ER-negative breast cancers are less differentiated, more aggressive, and often have a poor prognosis compared to the other breast cancer subtypes.”

Drs. Costes and Jonathan Tang, also with Berkeley Lab’s Life Sciences Division, were part of a collaboration led by Dr. Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine (New York, NY, USA), that studied the so-called “window of susceptibility” known to exist between radiation treatments at puberty and breast cancer risk in later adulthood. The key to their success were two mammary lineage agent-based models (ABMs) they developed in which a system is modeled as a collection of autonomous decision-making units called agents. One ABM simulated the effects of radiation on the mammary gland during either the developmental stages or during adulthood. The other simulated the growth dynamics of human mammary epithelial cells in culture after irradiation.

“Our mammary gland ABM consisted of millions of agents, with each agent representing either a mammary stem cell, a progenitor cell or a differentiated cell in the breast,” stated Dr. Tang. “We ran thousands of simulations on Berkeley Lab’s Lawrencium supercomputer during which each agent continually assessed its situation and made decisions on the basis of a set of rules that correspond to known or hypothesized biological properties of mammary cells. The advantage of this approach is that it allows us to view the global consequences to the system that emerge over time from our assumptions about the individual agents. To our knowledge, our mammary gland model is the first multiscale model of the development of full glands starting from the onset of puberty all the way to adulthood.”

Epidemiologic research have shown that girls under 20 administered radiotherapy treatment for disorders such as Hodgkin’s lymphoma have about the same risk of developing breast cancer in their 40s as women who were born with a BRCA gene mutation. From their study, Drs. Costes, Tang, and their colleagues concluded that self-renewal of stem cells was the most likely responsible process.

“Stem cell self-renewal was the only mechanism in the mammary gland model that led to predictions that were consistent with data from both our in vivo mouse work and our in vitro experiments with MCF10A, a human mammary epithelial cell line,” Dr. Tang noted. “Additionally, our model predicts that this mechanism would only generate more stem cells during puberty while the gland is developing and considerable cell proliferation is taking place.”

The investigators are now looking for genetic or phenotypic biomarkers that would identify young girls who are at the greatest breast cancer risk from radiotherapy. The study’s findings from Dr. Barcellos-Hoff and her research group show that the ties between ionizing radiation and breast cancer extend beyond DNA damage and mutations.

“Essentially, exposure of the breast to ionizing radiation generates an overall biochemical signal that tells the system something bad happened,” Dr. Costes said. “If exposure takes place during puberty, this signal triggers a regenerative response leading to a larger pool of stem cells, thereby increasing the chance of developing aggressive ER-negative breast cancers later in life.”

The findings of this collaborative study have been published online August 23, 2013, in the journal Stem Cells.

Related Links:

Lawrence Berkeley US National Lab’s Life Sciences Division


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83 (184.05914306641): SELECT show_live FROM jos_com_show_setting LIMIT 1
84 (313.04359436035): SELECT show_live FROM jos_com_show_setting LIMIT 1
85 (144.95849609375): SELECT show_live FROM jos_com_show_setting LIMIT 1
86 (33.140182495117): SELECT show_live FROM jos_com_show_setting LIMIT 1
87 (!!!!! 1245.0218200684): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
88 (!!!!! 1163.9595031738): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
89 (468.96934509277): SELECT id,name,title FROM jos_deeppockets WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id != 294743300 AND id != 294743301 AND id != 294743302 AND id != 294743303 AND id != 294743304 AND id != 294743305 AND id != 294743306 AND id != 294743307 AND id != 294743308 AND id != 294743309 AND id != 294743310 AND metakey != 'aacc' ORDER BY `ordering`
90 (!!!!! 8885.8604431152): SELECT show_live FROM jos_com_show_setting LIMIT 1
91 (413.89465332031): SELECT show_live FROM jos_com_show_setting LIMIT 1
92 (545.97854614258): SELECT show_live FROM jos_com_show_setting LIMIT 1
93 (150.91896057129): SELECT show_live FROM jos_com_show_setting LIMIT 1
94 (444.17381286621): SELECT show_live FROM jos_com_show_setting LIMIT 1
95 (36.954879760742): SELECT show_live FROM jos_com_show_setting LIMIT 1
96 (!!!!! 1451.9691467285): SELECT show_live FROM jos_com_show_setting LIMIT 1
97 (!!!!! 4194.0212249756): SELECT show_live FROM jos_com_show_setting LIMIT 1
98 (463.96255493164): SELECT show_live FROM jos_com_show_setting LIMIT 1
99 (396.9669342041): SELECT show_live FROM jos_com_show_setting LIMIT 1
100 (43.153762817383): SELECT show_live FROM jos_com_show_setting LIMIT 1
101 (902.89115905762): SELECT show_live FROM jos_com_show_setting LIMIT 1
102 (288.00964355469): SELECT show_live FROM jos_com_show_setting LIMIT 1
103 (349.99847412109): SELECT show_live FROM jos_com_show_setting LIMIT 1
104 (!!!!! 4581.9282531738): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
105 (!!!!! 2026.0810852051): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
106 (!!!!! 9721.9944000244): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
107 (!!!!! 8095.9796905518): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
108 (!!!!! 7290.1248931885): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
109 (!!!!! 7740.0207519531): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
110 (427.0076751709): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
111 (746.9654083252): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
112 (!!!!! 1045.9423065186): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1
113 (!!!!! 1109.8384857178): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1
114 (915.0505065918): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
115 (497.81799316406): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
116 (!!!!! 3305.9120178223): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
117 (349.99847412109): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
118 (458.0020904541): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
119 (261.06834411621): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
120 (364.06517028809): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
121 (66.041946411133): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
122 (581.97975158691): SELECT * FROM trending_articles WHERE `journal_id` = 10 AND `timestamp` <= NOW() + INTERVAL 7 DAY ORDER BY `order`
123 (!!!!! 105926.99050903): SELECT * FROM jos_deeppockets WHERE jos_deeppockets.cat = 10 AND jos_deeppockets.type = 'deeppockets_item' AND jos_deeppockets.published = 1 AND jos_deeppockets.created + INTERVAL 14 DAY >= NOW() ORDER BY jos_deeppockets.hits DESC LIMIT 7
124 (567.91305541992): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294748491 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294748491 AND type='deeppockets_item' AND published='1' LIMIT 1
125 (119.92454528809): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3
126 (36.954879760742): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3
127 (50.067901611328): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1
128 (31.948089599609): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1
129 (38.862228393555): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1
130 (29.087066650391): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1
131 (29.087066650391): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1
132 (28.848648071289): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1
133 (36.001205444336): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1
134 (28.848648071289): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1
135 (848.05488586426): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
136 (674.00932312012): SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
137 (181.91337585449): SELECT name FROM jos_deeppockets WHERE id=211
138 (44.107437133789): SELECT name FROM jos_deeppockets WHERE id=211
139 (746.9654083252): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))211((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3
140 (761.98577880859): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))211((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3
141 (401.02005004883): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
142 (77.962875366211): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
143 (!!!!! 14132.022857666): TRUNCATE TABLE jos_trademed_module
144 (188.11225891113): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
145 (!!!!! 1514.196395874): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294748491 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1
146 (967.02575683594): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
147 (138.0443572998): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1
148 (252.00843811035): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
149 (147.10426330566): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
150 (!!!!! 1494.8844909668): SELECT jos_item.* FROM jos_item INNER JOIN jos_number ON jos_item.numberID=jos_number.id WHERE 1=1 AND (jos_item.imgMini<>'') AND jos_item.type='L' AND jos_item.numberID= ( SELECT jos_number.id FROM jos_number WHERE jos_number.journalID IN (10) and jos_number.id in (select distinct jos_number.id from jos_number join jos_item on jos_item.numberid=jos_number.id where jos_item.type='P') ORDER BY (CONVERT(SUBSTRING(issue,1,2),SIGNED) + (CONVERT(SUBSTRING(issue,3,2),SIGNED)*100)) DESC LIMIT 0,1 ) ORDER BY RAND() DESC LIMIT 6
151 (178.09867858887): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
152 (95.129013061523): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
153 (123.97766113281): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294748491 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294748491 AND type='deeppockets_item' AND published='1' LIMIT 1
154 (78.916549682617): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=211 or channel_id is null)
155 (36.954879760742): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=211 or channel_id is null)
156 (479.93659973145): SELECT livesite FROM jos_dp_categories WHERE id=10 AND published='1' LIMIT 1
157 (404.83474731445): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
158 (101.08947753906): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294748491 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294748491 AND published='1' LIMIT 1
159 (56.982040405273): select jos_twitters.link from jos_twitters where cat=10
160 (30.040740966797): select jos_facebook.link from jos_facebook where cat=10
161 (30.040740966797): select jos_google_plus.link from jos_google_plus where cat=10
162 (30.040740966797): select jos_linkedin.link from jos_linkedin where cat=10