title: Estrogen withdrawal, increased breast cancer risk and the KRAS-variant.
abstract: The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42-37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.
authors.affiliation: a National University of Ireland ; Galway , Ireland.
authors.forename: Terri P
authors.initials: TP
authors.lastname: McVeigh
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Jung
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kerin
authors.forename: David W
authors.initials: DW
authors.lastname: Salzman
authors.forename: Sunitha
authors.initials: S
authors.lastname: Nallur
authors.forename: Antonio A
authors.initials: AA
authors.lastname: Nemec
authors.forename: Michelle
authors.initials: M
authors.lastname: Dookwah
authors.forename: Jackie
authors.initials: J
authors.lastname: Sadofsky
authors.forename: Trupti
authors.initials: T
authors.lastname: Paranjape
authors.forename: Olivia
authors.initials: O
authors.lastname: Kelly
authors.forename: Elcie
authors.initials: E
authors.lastname: Chan
authors.forename: Nicola
authors.initials: N
authors.lastname: Miller
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Sweeney
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.forename: Joann
authors.initials: J
authors.lastname: Sweasy
authors.forename: Robert
authors.initials: R
authors.lastname: Pilarski
authors.forename: Donatello
authors.initials: D
authors.lastname: Telesca
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015914:Estrogen Replacement Therapy / Q000639:trends; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D004967:Estrogens; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS-variant; breast cancer risk; estrogen withdrawal; multiple primary breast cancer; triple negative breast cancer; tumor biology